X-21940837-C-T

Variant names:

• chrX-21940837-C-T
• rs1921698887
• NM_004595.5:c.13C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_004595.5(SMS):​c.13C>T​(p.Arg5Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.9e-7 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SMS NM_004595.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0280
• Publications: 0 publications found

Genes affected

SMS (HGNC:11123): (spermine synthase) This gene encodes a protein belonging to the spermidine/spermin synthase family and catalyzes the production of spermine from spermidine. Pseudogenes of this gene are located on chromosomes 1, 5, 6 and X. Mutations in this gene cause an X-linked intellectual disability called Snyder-Robinson Syndrome (SRS). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

SMS Gene-Disease associations (from GenCC):

• syndromic X-linked intellectual disability Snyder type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 19 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 2.3162 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to syndromic X-linked intellectual disability Snyder type.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25726786).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMS	NM_004595.5	c.13C>T	p.Arg5Trp	missense_variant	Exon 1 of 11	ENST00000404933.7	NP_004586.2
SMS	NM_001258423.2	c.13C>T	p.Arg5Trp	missense_variant	Exon 1 of 9		NP_001245352.1
SMS	XM_011545568.3	c.-584C>T		upstream_gene_variant			XP_011543870.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMS	ENST00000404933.7	c.13C>T	p.Arg5Trp	missense_variant	Exon 1 of 11	1	NM_004595.5	ENSP00000385746.2
SMS	ENST00000379404.5	c.13C>T	p.Arg5Trp	missense_variant	Exon 1 of 9	3		ENSP00000368714.1
SMS	ENST00000478094.1	n.60C>T		non_coding_transcript_exon_variant	Exon 1 of 5	4
SMS	ENST00000457085.2	c.-137C>T		upstream_gene_variant		5		ENSP00000407366.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.93e-7 AC: 1 AN: 1007308 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 323194

African (AFR) AF: 0.00 AC: 0 AN: 21499

American (AMR) AF: 0.00 AC: 0 AN: 25272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17392

East Asian (EAS) AF: 0.00 AC: 0 AN: 23611

South Asian (SAS) AF: 0.00 AC: 0 AN: 47536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25445

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2727

European-Non Finnish (NFE) AF: 0.00000125 AC: 1 AN: 801537

Other (OTH) AF: 0.00 AC: 0 AN: 42289

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

SMS-related disorder Uncertain:1

Dec 09, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SMS c.13C>T variant is predicted to result in the amino acid substitution p.Arg5Trp. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.062	T;.
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.64	T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.49	N;N
PhyloP100		-0.028
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.21
Sift	Benign	0.094	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.0070	B;B
Vest4		0.19
MutPred		0.29		Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);
MVP		0.51
MPC		0.93
ClinPred		0.72	D
GERP RS		1.5
PromoterAI		-0.011	Neutral
Varity_R		0.31
gMVP		0.66
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1921698887; hg19: chrX-21958955;